The broad objective of this investigation is the definition of mechanisms of cardiac hypertrophy and failure. Previous observations suggest that patients free of evidence of coronary disease with long-standing mitral valve insufficiency (volume overload) may fail to improve following replacement of the mitral valves because of continued depressed left ventricular (LV) contractility. Our preliminary observations regarding function of the cardiac sarcoplasmic reticulum of papillary muscles removed in the course of mitral valve replacement suggest that duration of the cardiac symptoms may be related to the depression of the binding of calcium to the sarcoplasmic reticulum (S-R). Previous investigation in experimental animal models of pressure overload and potassium depletion cardiomyopathy revealed pathophysiologic changes in mitochondrial and S-R function not evident in a model of volume overload hypertrophy. Investigation of subcellular function will be done in cardiac muscle from 3 groups of patients: (1) acute volume overload of the LV, (2) chronic volume overload of the LV, (3) chronic pressure overload of the right ventricle (control). The specific aims of this proposal are: (1) to characterize kinetics of S-R calcium binding and uptake, (2) to assess mitochondrial state 4 oxygen consumption in the presence and absence of calcium ion transport inhibitors, (3) to quantitate the extent of myocardial fibrosis in left ventricular papillary muscle obtained at cardiopulmonary bypass surgery, 4 min. after aortic cross clamping, and (4) to quantitate the rate of left ventricular wall thickening. S-R calcium transport function will be assessed by millipore filtration. State 4 respiration of mitochondria will be characterized utilizing a vibrating oxygen electrode. Cardiac fibrosis will be evaluated by an operator-interactive computerized method designed to quantitate interstitial space. Finally, the left ventricular contractile characteristics will be defined by a method of videometry. Data developed by these methods may provide definitive evidence to support the hypothesis that as volume overload increases in duration and severity, pathophysiologic changes occur in the calcium transport systems of sarcoplasmic reticulum and mitochondria leading to irreversible myocardial cell damage.